This is a prospective, multi-center, open-label, phase Ib/ II study (two parts) with patients that have locally advanced or metastatic HER2+ breast cancer. The first part (phase Ib) will investigate the MTD/ RP2D of the combination therapy of BEZ235 BID and weekly trastuzumab using a Bayesian model. Once MTD/ RP2D is established the second part (phase II) will start. Phase II will evaluate the efficacy and the safety of weekly trastuzumab plus BEZ235 BID compared to capecitabine and lapatinib.

DLT is defined as treatment-related toxicity (classified according Common Toxicity Criteria for Adverse Events (CTCAE) Version 4) occurring during the first 28 treatment days and meeting specific protocol-predefined criteria.

The information will be integrated in a Bayesian logistic regression model with overdose control to estimate the maximum tolerated dose (MTD)

PFS is defined as the time from randomization until objective tumor progression or death from any cause. Radiological assessments will be performed every 6 weeks for the first 36 weeks after treatment start, then every 12 weeks.

Time from treatment start until objective tumor progression or death from any cause. Radiological assessments will be performed every 8 weeks for the first 32 weeks after treatment start, then every 12 weeks.

Overall Response Rate (ORR)- Phase lb [ Time Frame: 12 months ]

Proportion of patients with a best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1

Clinical Benefit Rate (CBR) (Phase lb) [ Time Frame: 12 months ]

Proportion of patients with a best overall response of CR, PR or stable disease (SD) with a duration of 24 weeks or longer according to RECIST 1.1

Frequency and severity of Adverse Events - Phase lb [ Time Frame: until 30 days after treatment discontinuation ]

Incidence of adverse events (based on common terminology criteria for adverse events (CTCAE) Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment.

BEZ235 plasma and trastuzumab serum concentrations obtained during the two sampling windows (pre-dose and post-dose). No pharmacokinetic parameters will be calculated and no formal statistical analysis will be performed.

Overall Response Rate (ORR) - phase ll [ Time Frame: 12 months ]

Proportion of patients with a best overall response of CR or PR according to RECIST 1.1

Clinical Benefit Rate (CBR) - phase ll [ Time Frame: 12 months ]

Proportion of patients with a best overall response of CR, PR or SD with a duration of 24 weeks or longer according to RECIST 1.1

Time from randomization until objective tumor progression or death from any cause. Radiological assessments will be performed every 6 weeks for the first 36 weeks after treatment start, then every 12 weeks, centrally collected and read.

Frequency and severity of adverse events (phase ll) [ Time Frame: Until 30 days after treatment discontinuation ]

Incidence of adverse events (based on CTCAE Version 4) summarized by system organ class and/or preferred term, severity and relation to study treatment.

Phase l: Patients will receive increasing doses of oral BEZ235 (BID) together with standard weekly trastuzumab at a fixed dose. BEZ235 doses will be escalated in cohorts of 3 to 6 patients guided by an adaptive Bayesian logistic regression model with overdose control until MTD/RP2D has been established.

Phase ll: If randomized to the trastuzumab + BEZ235 arm, patients will receive standard weekly trastuzumab in combination with oral BEZ235 (BID) at the MTD or RP2D and will continue on study treatment until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met. They will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy).

Active Comparator: Lapatinib + Capecitabine (Phase II)

Eligible patients will receive lapatinib (1250 mg given orally once daily on days 1 through 21) in combination with capecitabine (2000 mg/m2/day administered orally in 2 doses approximately 12 hours apart on days 1 through 14). Treatment will be organized into cycles of 21 days .

Drug: Lapatinib + Capecitabine (Phase II)

If randomized to the lapatinib + capecitabine treatment arm, patients will receive standard lapatinib plus capecitabine until PD, unacceptable toxicity or until other pre-defined discontinuation criteria are met.

Patients will have regular safety assessments and will be evaluated for response to treatment according to RECIST every 2 cycles for the first 36 weeks then every 12 weeks until disease progression (or start of new anti-neoplastic therapy). After progression, survival f-up will continue.

All patients participating in the Phase II part of the study will be required to have available archival or fresh tumor tissue for biomarker analysis prior to treatment start

Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235

Treatment at start of study treatment with drugs with a known risk to induce Torsades de Pointes, moderate and strong inhibitors or inducers of isoenzyme CYP3A4, warfarin and coumadin analogues, LHRH agonists

Intolerance or contraindications to trastuzumab treatment

Pregnant or nursing (lactating) woman

Additional exclusion criteria for phase II:

Prior treatment with capecitabine and lapatinib

Intolerance or contraindications to capecitabine and lapatinib

Previous treatment with HER-2 targeted agents other than trastuzumab or T-DM1

Peripheral neuropathy ≥ Grade 2

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01471847